Bicalutamide represented by the formula (I):
(hereinafter sometimes referred to as compound of the formula (I) or compound (I) in the present specification) has been reported to be useful as a compound having an antiangrogenic action (JP-B-4-32061, U.S. Pat. No. 4,636,505 and WO01/34563). As a synthetic method of the compound of the formula (I), for example, a method comprising a reaction of 4′-cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide represented by the formula (3):
(hereinafter sometimes referred to as compound of the formula (3) or compound (3)) in methylene chloride solution with m-chloroperbenzoic acid is known (Howard Tucker et al, J. Med. Chem., Vol. 31, 954–959 (1988), and WO01/28990). In this method, methylene chloride is used as a solvent. Halogenated organic solvents such as methylene chloride and the like are generally harmful for human body, and the possibility of carcinogenicity thereof has been suggested. Furthermore, they may produce dioxin during waste treatments. Halogenated organic solvents such as methylene chloride and the like are associated with the problems of economic burden for the cost of waste treatment after use, and of corrosion of incinerator used for the waste treatment.
In recent years, “Green Chemistry” has been drawing attention as one of the measures for risk reduction of chemical substances, and industrial application of environmentally benign type chemical reactions (or reaction not using substances potentially harmful to human body and the environment (e.g., halogen-containing substances etc.) as much as possible, and not emitting them as much as possible) has become a very important object. From this aspect, the above-mentioned production method using methylene chloride as an organic solvent is not entirely a preferable production method of bicalutamide. Therefore, the development of a production method of bicalutamide, which is superior in environmental benignity, is desired.
In addition, the above-mentioned method uses m-chloroperbenzoic acid as an oxidizing agent. m-Chloroperbenzoic acid is highly explosive and is not preferable for industrial processes. Furthermore, m-chloroperbenzoic acid is expensive and poses an economic problem.
Accordingly, industrial practice of the above-mentioned method at a large scale gives rise to the problems not only in environmental benignity, but also safety and economic aspect, due to the use of a halogenated organic solvent as the solvent and of m-chloroperbenzoic acid as the oxidizing agent.
At the moment, as a synthetic method of bicalutamide, which is free of the use of m-chloroperbenzoic acid as an oxidizing agent, the method described in, for example, WO01/00608 is known. According to this method, compound (3) is oxidized with aqueous hydrogen peroxide as an oxidizing agent, in acetic acid or formic acid, for the synthesis of bicalutamide. Thus, this method is considered to be environmentally, economically and industrially superior. In this method, however, synthesis of precursor compound (3) requires many steps (at least 4 steps), which makes this method not an economically and industrially superior synthetic method for the total synthesis of bicalutamide. Furthermore, this method includes steps using a halogenated solvent (e.g., methylene chloride etc.) for the synthesis of compound (3). Thus, it is difficult to say that this method is sufficiently environmentally conscious.
As a synthetic method of bicalutamide free of use of m-chloroperbenzoic acid as an oxidizing agent, a method described in WO02/24638 is also known. The method described in WO02/24638 includes adding aqueous hydrogen peroxide to compound (3), cooling (e.g., −55° C.) the mixture, and adding trifluoroacetic anhydride to the mixture to give bicalutamide. However, this method uses expensive trifluoroacetic anhydride as a reagent, and requires cooling when trifluoroacetic anhydride is added, and is not an economically superior method. Furthermore, because of the corrosive and hygroscopic property of trifluoroacetic anhydride, the method is unsuitable for the industrial production of bicalutamide.
Accordingly, the development of an economical and industrially practical production method of bicalutamide, which is superior in environmental benignity and safety, is desired in this field.
For efficient granulation of a crystal in the field of the production of pharmaceutical drugs, it is desirable that the form of the crystal be defined. However, the form of the crystal of bicalutamide is not defined in any of the above-mentioned references, and therefore, those of ordinary skill in the art of the production of pharmaceutical drugs strongly desire provision of bicalutamide crystals having a defined form.